chr14-36519723-A-AAGAG

Variant names:

• chr14-36519723-A-AAGAG
• rs149047715
• NM_001079668.3:c.77+326_77+329dupCTCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001079668.3(NKX2-1):​c.77+326_77+329dupCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000579 in 1,450,536 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: NKX2-1 NM_001079668.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.683

Genes affected

NKX2-1 (HGNC:11825): (NK2 homeobox 1) This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]

SFTA3 (HGNC:):

NKX2-1-AS1 (HGNC:40585): (NKX2-1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000198 (3/151188) while in subpopulation NFE AF= 0.0000443 (3/67668). AF 95% confidence interval is 0.0000118. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.77+326_77+329dupCTCT		intron_variant	Intron 1 of 2	ENST00000354822.7	NP_001073136.1
NKX2-1-AS1	NR_103710.1	n.402+57_402+60dupAGAG		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.77+329_77+330insCTCT		intron_variant	Intron 1 of 2	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.-13-354_-13-353insCTCT		intron_variant	Intron 1 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 151080 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 81 AN: 1299348 Hom.: 0 Cov.: 28 AF XY: 0.0000659 AC XY: 42 AN XY: 637198

Gnomad4 AFR exome AF: 0.0000339

Gnomad4 AMR exome AF: 0.000187

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000316

Gnomad4 SAS exome AF: 0.0000275

Gnomad4 FIN exome AF: 0.0000678

Gnomad4 NFE exome AF: 0.0000616

Gnomad4 OTH exome AF: 0.0000558

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151188 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3 AN XY: 73844

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149047715; hg19: chr14-36988928;